NMJ

Question 1

What does the somatic nervous system activate?

Answer 1

Skeletal muscle contraction

Question 2

How is the somatic nervous system regulated?

Answer 2

By corticospinal tracts and spinal reflexes

Question 3

Somatic synapses?

Answer 3

One at NMJ - ACh –> nicotinic receptor

Question 4

Parasympathetic synapses?

Answer 4

Long preganglionic - ACh –> nicotinic receptor

Short postganglionic - ACh –> muscarinic receptor

Question 5

Sympathetic synapses?

Answer 5

Short preganglionic - ACh –> nicotinic receptor
Long postganglionic - NE –> adrenergic receptors

(sweat glands ACh –> muscarinic)

Question 6

What does the autonomic nervous system activate?

Answer 6

Smooth muscle
Exocrine glands
Cardiac tissue
Metabolic activities

Question 7

How is the autonomic nervous system regulated?

Answer 7

By brain stem centres

Question 8

Outline the structure of a nicotinic receptor

Answer 8

Ligand gated ion channel
Requires the binding of 2 ACh molecules.
5 subunits.

Upon binding, the 2nm channel opens wider due to conformational changes.

Question 9

Composition of NM/N1 form?

Answer 9

a1 x 2
b1
delta
epsilon (gamma in embryonic)

Question 10

Composition of NN/N2 form?

Answer 10

a2-10

b2-4

Question 11

What is the NMJ?

Answer 11

Specialised form of synaptic transmission between neurons and skeletal muscle to cause muscle contraction

Question 12

What causes the release of neurotransmitter?

Answer 12

Motor neuron depolarisation causes the action potential to travel down the nerve fibre to the NMJ.
Depolarisation of the axon terminal causes an influx of Ca2+
Triggers fusion of synaptic vesicles and release of ACh (neurotransmitter)

Question 13

What does the neurotransmitter cause?

Answer 13

ACh binds to postsynaptic ACh receptor on the muscle fibre at the motor end plate
Binding opens the channels, causing an influx of sodium ions.
Depolarisation occurs on the sarcolemma and travels down the T tubules to cause the release of Ca2+ from the sarcoplasmic reticulum - contraction

Question 14

What happens to the ACh?

Answer 14

Ubound ACh diffuses away or is hydrolysed by AChE

Question 15

Outline Myasthenia gravis?

Answer 15

Autoantibodies to the nicotinic ACh receptors on the motor end plates of muscles. Binding of ACh is blocked. Also induce complement-mediated degradation of the receptors, resulting in progressive weakening of the skeletal muscles.

Autoantibodies to MuSK which is important for the tight clustering of receptors at the NMJ

Question 16

Symptoms of Myasthenia gravis?

Answer 16

Weakness of eye muscles, swallowing and slurred speech.

Eye movement, facial expressions, chewing, talking, swallowing.

Breathing and neck movements.

Question 17

Describe Lambert-Eaton myasthenic syndrome?

Answer 17

Autoantibodies to presynaptic voltage gated calcium channel (VGCC)

Interfere with the calcium dependent release of ACh from the presynaptic membrane and cause a reduced endplate potential on the postsynaptic membrane

Question 18

Describe Neuromyotonia (Isaac’s syndrome)?

Answer 18

Autoantibodies to presynaptic voltage gated potassium channels (VGKC).
Results in continuous excitability.

Question 19

Main drugs involved at NMJ?

Answer 19

ACh blocking agents

Anticholinesterases (increases ACh - all others block/decrease)

Drugs affecting synthesis and storage of axonal ACh

Question 20

Active compound in curare?

Answer 20

d-tubocararine
skeletal muscle paralysis
blocks ACh binding to the receptor

Non depolarising blocking agent.

Question 21

Subclasses of neuromuscular blocking drugs?

Answer 21

Depolarising and non-depolarising

Question 22

Mechanism of non depolarising blockers?

Answer 22

Prevents the opening of the channel when it competitively binds to the receptor.
Can be reversed.

Question 23

Rocuronium?

Answer 23

Non depolarising blocker

Question 24

Mechanism of depolarising blockers?

Answer 24

Occupy the receptor site, opening the channel and block the channel.
Normal closure of the gate is prevented and the blocker can move into the pore.
May desensitise the end plate by causing persistent depolarisation

Question 25

Succinylcholine?

Answer 25

Depolarising blocker

Question 26

Cobratoxin and a-bungarotoxin?

Answer 26

Bind with high affinity to the nicotinic receptors, causing a postsynaptic block at the NMJ

Question 27

Effects of NMJ blocking agents?

Answer 27

Paralysis from the small rapidly moving muscles to limbs then respiratory muscles

Question 28

Non depolarising agents effect?

Answer 28

Flaccid, relaxed paralysis. Can be reversed by AChE inhibitors. Histamine release. Muscarinic blocking.

Question 29

Depolarising agents effect?

Answer 29

Phase 1 - membrane depolarisation, transient fasiculations --> paralysis Phase 2 - desensitisation. Membrane depolarises and is hypersensitive to ACh. Block can't be reversed

Question 30

Pancuronium?

Answer 30

Non depolarising blocking agent

Question 31

Gallamine?

Answer 31

Non depolarising blocking agent

Question 32

Mlvacurium?

Answer 32

Non depolarising blocking agent

Question 33

Atracurium?

Answer 33

Non depolairising blocking agent

Question 34

Clinical uses of NMJ blocking agents?

Answer 34

``` Muscle relaxation in surgety Orthopedics Facilitate intubations Facilitate internal exams Prevent trauma Diagnostic ```

Question 35

Uses of acetylcholinesterase inhibitors?

Answer 35

``` Myasthenia gravis treatment Alzheimer's Lewy body dementia Glaucoma Antidote for anticholinergic poisoning ```

Question 36

Types of acetylcholinesterase inhibitors?

Answer 36

Venoms & poisons | Nerve agents & insecticides

Question 37

Examples of acetylcholinesterase inhibitors?

Answer 37

Edrophonium Neostigmine Pyridostigmine Distigime

Question 38

Symptoms of NMJ overstimulation?

Answer 38

``` Vasodilation Sweating Salivation Bronchial secretions Miosis Flaccid paralysis Respiratory failure. ```

Question 39

Nerve gas poisoning?

Answer 39

Atropine - antidote, blocks ACh from binding | Oximes can regenerate the enzymes

Question 40

Organophosphates?

Answer 40

Irreversible acetylcholinesterase inhibitors phosphorus atom covalently binds to a serine hydroxyl group in the active site pralidoxime reactives the enzmye

Question 41

Neostigmine?

Answer 41

AChE inhibitor which permits buildup of ACh for more intensive and prolonged activation. Time prolonged to interact with receptors that are not blocked by autoantibodies

Question 42

Edrophonium?

Answer 42

Readily reversible AChE inhibitor. True competitive inhibition. Can be used to differentiate myasthenic from cholinergic crisis.

Question 43

Myasthenic crisis?

Answer 43

Not enough NM stimulation. Edrophonium will reduce muscle weakness by supplying more ACh

Question 44

Cholinergic crisis?

Answer 44

Too much NM stimulation. Will make weakness worse by inducing a depolarising block.

Question 45

Physostigmine?

Answer 45

Reversible pseudocompetitive AChE inhibitor. Treat myasthenia gravis, Alzheimer's and delayed gastrice emptying Crosses BBB

Question 46

AChE inhbitors to treat dementia?

Answer 46

hypothesis - cognitive decline is linked to hippocampus and cortex.

Question 47

SNARE proteins?

Answer 47

allow vesicles to release AC into NMJ. | Botox cleaves specific SNARE proteins to block the vesicles from releasing ACh.